Chemists at MIT have created a triple warhead against cancer. They believe theirs is the first example a polymer nanoparticle which carries a precise ratio of three drugs that can be released in response to three distinct triggers.
They loaded the three drugs, commonly used to treat ovarian cancer, using a unique approach, according to an article in Journal of the American Chemical Society . Instead of trapping the drugs within the nanoparticle or binding the drug chemically, they started with building blocks with drug molecules already attached.
“We then just start building from those blocks. We don’t ever attach anything and or encapsulate anything [in a preformed nanoparticle],” explains lead author Jeremiah Johnson , a chemist at MIT. The three parts to each block are the drug, a linker and polyethylene glycol (PEG). They then add blocks together akin to building Lego.
“In this recent paper we are using 3 building blocks, but in my lab we have built up to 15 different building blocks, each with a different drug, and link them to various monomers to control the release rate,” Johnson explains. Animal tests are being carried out on the triple cancer drug combination, but the group is also synthesising a four-drug cocktail for use against pancreatic cancer and has begun animal work there too.
Delivering chemotherapy in nanoparticle form could help reduce side effects by landing the drugs directly onto tumour targets. In recent years, nanoparticles have been developed that are capable of delivering one or may two chemistry therapy drugs, but it has been difficult to design particles that can carry more.
“These other methods are great for one or two things, but limited once you increase the complexity and add more things. We took the approach of having building blocks with the drugs already attached to them, so we just build up from those blocks,” Johnson told In-Pharmatechnologist. He says people have asked also about delivering peptides, antimicrobials or other combinations of drugs and the answer is yes, though it hasn’t been their focus.
“In principle there’s no limitation on how many drugs you can add, and the ratio of drugs carried by the particles just depends on how they are mixed together in the beginning,” Johnson explains. For their most recent paper, particles were created that carried the drugs cisplatin, doxorubicin and camptothecin, which are often used alone or in combination to treat ovarian cancer.
Each particle carried the three drugs in a specific ratio matching the maximum tolerated dose of each drug, and each drug had its own release mechanism. Cisplatin is freed as soon as the particle enters a cell, due to an anti-oxidant. Captothecin is released quickly when it encounters esterase enzymes; doxorubicin is released when UV light shines on the particle. Only PEG remains and that is biodegradable.
PEG makes everything soluble and easy to work with, allowing us to mix and match, Johnson explains, and it helps the particles avoid the immune system.